Prion diseases are neurodegenerative disorders of humans and animals. These diseases can present as genetic, infectious or sporadic illnesses and are often transmissible to experimental animals. Convergence of many lines of experimental evidence asserts that the scrapie isoform of the prion protein (PrP/Sc) is a necessary component of the infectious scrapie prion yet both PrP/Sc and the normal isoform, PrP/C, are encoded by the same chromosomal gene. All attempts to identify a candidate scrapie- specific nucleic acid in fractions enriched for scrapie infectivity have failed. Seven senior investigators with outstanding records of accomplishment in a variety of scientific disciplines and with demonstrated commitments to scrapie research propose to extend their collaborative studies currently supported by an NINDS-Program Project Grant. The exciting progress in scrapie research over the past five years coupled with the complementary talents and skills of this group of scientists represents a unique opportunity to make further advances by taking advantage of some unprecedented discoveries in prion diseases. Molecular genetic studies in sheep, mice and humans have shown that susceptibility to prion diseases--natural scrapie of sheep, experimental scrapie in mice as well as Gerstmann-Straussler (GSS) and Creutzfeldt- Jakob diseases (CJD) in humans--is genetically linked to amino acid substitutions in the open reading frame of the prion protein (PrP) gene. Studies with congenic and Tg mice expressing different numbers of the a and b alleles of mouse (Mo) PrP have shown that long incubation times are not dominant traits but rather result from the effects of PrP gene dosage. These findings overturned one of the major tenets which were established in scrapie research over the past 25 years. Highly sensitive techniques for detecting low concentrations of nucleic acids have been developed but no scrapie specific candidate polynucleotide has been found. These results are of considerable importance, as the number of hypotheses available to explain strains of prions continues to shrink. Construction of chimeric transgenes has given us a new system for the study of the human (Hu) prion diseases; Tg(MHu2M) mice expressing the chimeric Hu/Mo PrP are susceptible to Hu prions. The infrequent transmission of prion disease to Tg(HuPrP) mice in contrast to Tg(MHu2M) mice argues that a species-specific factor which we have provisionally designated as protein X governs the conversion of PrP/C into PrP/Sc. Whether protein X is molecular chaperone remains to be determined. Chimeric and tagged PrP/Sc molecules will be employed in the studies designed to unravel the enigma of prion strains. The molecular basis of prion "strains" presents a fascinating conundrum; studies of strains may be facilitated by using chimeric PrP molecules, especially if different prion strains prove to be distinct conformers of PrP/Sc. Our studies may ultimately elucidate the mechanisms responsible for a variety of CNS degenerative disorders, in particular those of unknown etiology afflicting older people such as Alzheimer's disease.